Interstate 35 (I-35) is a north–south Interstate Highway in the United States that runs from Laredo, Texas, to Duluth, Minnesota. In Iowa, the highway runs from south to north through the center of the state, roughly parallel to U.S. Highway 69 (US 69) and US 65. It enters the state near Lamoni from Missouri and continues north through the southern Iowa drift plain. In the Des Moines area, I-35 runs concurrently with I-80, and the two highways bypass Des Moines to the west and north. I-235, the only auxiliary route of I-35, serves the suburbs and downtown Des Moines; it begins and ends at the two interchanges where I-35 and I-80 meet. Near Mason City and Clear Lake, US 18 and Iowa Highway 27 (Iowa 27) overlap with I-35. Shortly after, US 18 splits off to the west in Clear Lake, while Iowa 27 runs with I-35 until they reach the Minnesota state line.

U.S. Highway 20 (US 20) in Iowa is a major east–west artery which runs across the state, separating the northern third of Iowa from the southern two-thirds. It enters Iowa from Nebraska, concurrent with Interstate 129 (I-129) and US 75, crossing the Missouri River at Sioux City. US 20 runs in a more-or-less straight line across Iowa, paralleling 42° 27' N. It leaves Iowa in Dubuque by crossing the Mississippi River into Illinois. Since October 2018, US 20 is a four-lane divided highway for its entire length in Iowa.